The invention relates to bioabsorbable materials, which are rendered antimicrobial due to the presence of antimicrobial metals in the form of coatings or powders; processes for their production; and use of same for controlling infection.
The risk of acquiring infections from bioabsorbable materials in medical devices is very high. Many medical applications exist for bioabsorbable materials including:
1) Wound Closures: including for example sutures, staples, adhesives;
2) Tissue Repair: including for example meshes for hernia repair;
3) Prosthetic Devices: including for example internal bone fixation, physical barrier for guided bone regeneration;
4) Tissue Engineering: including for example blood vessels, skin, bone, cartilage, and liver; and
5) Controlled Drug Delivery Systems: including for example microcapsules and ion-exchange resins.
The use of bioabsorbable materials in medical applications such as the above have the advantages of reducing tissue or cellular irritation and induction of inflammatory response from prominent retained hardware; eliminating or decreasing the necessity of hardware removal; and in the case of orthopedic implants, permitting a gradual stress transfer to the healing bone and thus allowing more complete remodeling of the bone.
Bioabsorbable materials for medical applications are well known; for example, U.S. Pat. No. 5,423,859 to Koyfman et al., lists exemplary bioabsorbable or biodegradable resins from which bioabsorbable materials for medical devices may be made. In general, bioabsorbable materials extend to synthetic bioabsorbable, naturally derived polymers, or combinations thereof, with examples as below:
1) Synthetic Bioabsorbable Polymers: for example polyesters/polylactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers; and
2) Naturally Derived Polymers:
a) Proteins: albumin, fibrin, collagen, elastin;
b) Polysaccharides: chitosan, alginates, hyaluronic acid; and
3) Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
Like other biomaterials, bioabsorbable materials are also subjected to bacterial contamination and can be a source of infections which are difficult to control. Those infections quite often lead to the failure of the devices, requiring their removal and costly antimicrobial treatments.
Prior art efforts to render bioabsorbable materials more infection resistant generally have focused on impregnating the materials with antibiotics or salts such as silver salts. However, such efforts usually provide only limited, and instantaneous antimicrobial activity, which is limited by the availability or solubility of the antimicrobial agent over time. It is desirable to have an antimicrobial effect which is sustained over time, such that the antimicrobial effect can be prolonged for the time that the bioabsorbable material is in place. This can range from hours or days, to weeks or even years.
There are suggestions in the prior at to provide metal coatings, such as silver coatings, on medical devices; for example, International Publication No. WO 92/13491 to Vidal and Redmond; Japanese Patent Application Disclosure No. 21912/85 to Mitsubishi Rayon K. K., Tokyo; and U.S. Pat. No. 4,167,045 to Sawyer. None of these references include teachings specific to the use of metal coatings on bioabsorbable materials. In such applications, it is important that the metal coatings do not shed or leave behind large metal particulates in the body, which will induce unwanted immune responses and/or toxic effects.
There is a need for antimicrobial coatings for bioabsorbable materials, which can create an effective and sustainable antimicrobial effect, which do not interfere with the bioabsorption of the bioabsorbable material, and which do not shed or leave behind large metal particulates in the body as the bioabsorbable material disappears.
This invention provides bioabsorbable materials comprising a bioabsorbable substrate associated with one or more antimicrobial metals being in a crystalline form characterized by sufficient atomic disorder, such that the bioabsorbable material in contact with an alcohol or water based electrolyte, releases atoms, ion, molecules, or clusters of at least one antimicrobial metal at a concentration sufficient to provide an antimicrobial effect. The one or more antimicrobial metals do not interfere with the bioabsorption of the bioabsorbable material, and do not leave behind particulates larger than 2 xcexcm, as measured 24 hours after the bioabsorbable material has disappeared. Most preferably, the particulate sizing from the coating or powder is sub-micron, that is less than about 1 xcexcm, as measured 24 hours after the bioabsorbable material has disappeared. Particulates are thus sized to avoid deleterious immune responses or toxic effects. Such antimicrobial metals are in the form of a continuous or discontinuous coating, a powder, or a coating on a bioabsorbable powder.
The antimicrobial coating is thin, preferably less than 900 nm or more preferably less than 500 nm, and very fine grained, with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm. The antimicrobial coating is formed of an antimicrobial metal, which is overall crystalline, but which is created with atomic disorder, and preferably also having either or both of a) a high oxygen content, as evidenced by a rest potential greater than about 225 mV, more preferably greater than about 250 mV, in 0.15 M Na2CO3 against a SCE (standard calomel electrode), or b) discontinuity in the coating.
The antimicrobial metal associated with the bioabsorbable substrate may also be in the form of a powder, having a particle size of less than 100 xcexcm or preferably less than 40 xcexcm, and with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm. Such powders may be prepared as a coating preferably of the above thickness, onto powdered biocompatible and bioabsorbable substrates; as a nanocrystalline coating and converted into a powder; or as a powder of the antimicrobial metal which is cold worked to impart atomic disorder.
A method of preparing the above antimicrobial bioabsorbable materials is also provided, with the bioabsorbable substrate being formed from a bioabsorbable polymer, or being a medical device or part of a medical device. The coating or powder of the one of more antimicrobial metals is formed by either physical vapour deposition under specified conditions and/or by forming the antimicrobial material as a composite material; or by cold working the antimicrobial material containing the antimicrobial metal at conditions which retain the atomic disorder, as in the case where the antimicrobial metal is in the form of a powder. Sufficient oxygen is incorporated in the coating or powder such that particulates of the antimicrobial metals during dissociation are sized at preferably less than 2 xcexcm, or preferably less than 1 xcexcm, to avoid deleterious immune responses or toxic effects,
As used herein, the terms and phrases set out below have the meanings which follow.
xe2x80x9cAlcohol or water-based electrolytexe2x80x9d is meant to include any alcohol or water-based electrolyte that the anti-microbial coatings of the present invention might contact in order to activate (i.e. cause the release of species of the anti-microbial metal) into same. The term is meant to include alcohols, saline, water, gels, fluids, solvents, and tissues containing water, including body fluids (for example blood, urine or saliva), and body tissue (for example skin, muscle or bone).
xe2x80x9cAntimicrobial effectxe2x80x9d means that atoms, ions, molecules or clusters of the anti-microbial metal (hereinafter xe2x80x9cspeciesxe2x80x9d of the anti-microbial metal) are released into the alcohol or electrolyte which the material contacts in concentrations sufficient to inhibit bacterial (or other microbial) growth in the vicinity of the material. The most common method of measuring anti-microbial effect is by measuring the zone of inhibition (ZOI) created when the material is placed on a bacterial lawn. A relatively small or no ZOI (ex. less than 1 mm) indicates a non useful anti-microbial effect, while a larger ZOI (ex. greater than 5 mm) indicates a highly useful anti-microbial effect. One procedure for a ZOI test is set out in the Examples which follow.
xe2x80x9cAntimicrobial metalsxe2x80x9d are metals whose ions have an anti-microbial effect and which are biocompatible. Preferred anti-microbial metals include Ag, Au, Pt, Pd, Ir (i.e., the noble metals), Sn, Cu, Sb, Bi and Zn, with Ag being most preferred.
xe2x80x9cAtomic disorderxe2x80x9d includes high concentrations of: point defects in a crystal lattice, vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, gain and sub grain boundaries and the like relative to its normal ordered crystalline state. Atomic disorder leads to irregularities in surface topography and inhomogeneities in the structure on a nanometer scale.
xe2x80x9cBioabsorbable materialsxe2x80x9d are those useful in medical devices or parts of medical devices, that is which are biocompatible, and which are capable of bioabsorption in a period of time ranging from hours to years, depending on the particular application.
xe2x80x9cBioabsorptionxe2x80x9d means the disappearance of materials from their initial application site in the body (human or mammalian) with or without degradation of the dispersed polymer molecules.
xe2x80x9cBiocompatiblexe2x80x9d means generating no significant undesirable host response for the intended utility.
xe2x80x9cCold workingxe2x80x9d as used herein indicates that the material has been mechanically worked such as by milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material. This ensures that atomic disorder imparted through working is retained in the material.
xe2x80x9cDiffusionxe2x80x9d, when used to describe conditions which limit diffusion in processes to create and retain atomic disorder, i.e. which freeze-in atomic disorder, means diffusion of atoms and/or molecules on the surface or in the matrix of the material being formed.
xe2x80x9cDissociationxe2x80x9d means the breakdown of the antimicrobial metal in the form of a coating or powder associated with the bioabsorbable substrate, when the bioabsorbable material is in contact with an alcohol or water based electrolyte.
xe2x80x9cGrain sizexe2x80x9d, or xe2x80x9ccrystallite sizexe2x80x9d means the size of the largest dimension of the crystals in the anti-microbial metal coating or powder.
xe2x80x9cMetalxe2x80x9d or xe2x80x9cmetalsxe2x80x9d includes one or more metals whether in the form of substantially pure metals alloys or compounds such as oxides, nitrides, borides, sulphides, halides or hydrides.
xe2x80x9cNanocrystallinexe2x80x9d is used herein to denote single-phase or multi-phase polycrystals, the grain size of which is less than about 100, more preferably  less than 50 and most preferably  less than 25 nanometers in at least one dimension. The term, as applied to the crystallite or grain size in the crystal lattice of coatings, powders or flakes of the anti-microbial metals, is not meant to restrict the particle size of the materials when used in a powder form.
xe2x80x9cNormal ordered crystalline statexe2x80x9d means the crystallinity normally found in bulk metal materials, alloys or compounds formed as cast, wrought or plated metal products. Such materials contain only low concentrations of such atomic defects as vacancies, grain boundaries and dislocations.
xe2x80x9cParticulate sizexe2x80x9d means the size of the largest dimension of the particulates which are shed or left behind in the body from the antimicrobial coatings on the bioabsorbable materials.
xe2x80x9cPowderxe2x80x9d is used herein to include particulate sizes of the nanocrystalline anti-microbial metals ranging from nanocrystalline powders to flakes
xe2x80x9cSustained releasexe2x80x9d or xe2x80x9csustainable basisxe2x80x9d are used to define release of atoms, molecules, ions or clusters of an anti-microbial metal that continues over time measured in hours or days, and thus distinguishes release of such metal species from the bulk metal, which release such species at a rate and concentration which is too low to achieve an anti-microbial effect and from highly soluble salts of anti-microbial metals such as silver nitrate, which releases silver ions virtually instantly, but not continuously, in contact with an alcohol or electrolyte.
A. Bioabsorbable Materials
Bioabsorbable materials for medical applications are well known, and include bioabsorbable polymers made from a variety of bioabsorbable resins; for example, U.S. Pat. No. 5,423,859 to Koyfman et al., lists exemplary bioabsorbable or biodegradable resins from which bioabsorbable materials for medical devices may be made. Bioabsorbable materials extend to synthetic bioabsorbable or naturally derived polymers, with typical examples as below:
1) Synthetic Bioabsorbable Polymers: for example polyesters/polylactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers,
2) Naturally Derived Polymers:
a) Proteins: albumin, fibrin, collagen, elastin;
b) Polysaccharides: chitosan, alginates, hyaluronic acid; and
3) Biosynthetic Polyesters: 3-hydroxybutyrate polymers
The bioabsorbable material, depending on the application, may be used in a powder, sheet or fibre form.
Many medical applications exist for bioabsorbable materials coated with the antimicrobial coatings of this invention, including, without limitation:
1) Wound closures: including for example sutures, staples, and adhesives,
2) Tissue Repair: including for example meshes for hernia repair;
3) Prosthetic Devices: including for example internal bone fixation, physical barrier for guided bone regeneration;
4) Tissue Engineering: including for example blood vessels, skin, bone, cartilage, and liver;
5) Controlled Drug Delivery Systems: including for example microcapsules and ion-exchange resins; and
6) Wound Coverings or Fillers: including for example alginate dressings and chitosan powders.
B. Antimicrobial Coating for Bioabsorbable Materials
The bioabsorbable material includes an antimicrobial coating formed from an antimicrobial metal, which is formed by the procedure set out below. The coating can be applied as one or more of the layers, but is most preferably applied as a discontinuous coating of a single thin layer which is less than 900 nm in thickness, more preferably less than 500 nm, and which has a grain size (i.e. crystallite size in the coating itself) less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm.
The coating is most preferably formed with atomic disorder in accordance with the procedures set out above and as described in International Publication Nos. WO 98/41095, WO 95/13704, and WO 93/23092, all to Burrell et al. In addition, the coating is preferably formed with a high oxygen content, as determined by a positive rest potential greater than 225 mV, more preferably greater than about 250 mV, in 0.15 M Na2CO3 against a SCE, when measured in accordance with the procedure set out in Example 5. The high oxygen content is achieved by including oxygen in the working gas atmosphere during the physical vapour deposition technique. Preferably the ratio of inert working gas (preferably argon) to oxygen is about 96:4 or less.
The antimicrobial coating can be rendered discontinuous by many techniques, for instance by coating fibers or powders from only one side, with or without rotation or vibration, by making the coatings so thin as to be discontinuous, by coating on porous fibrous materials so as to achieve discontinuity, by masking either the substrate or the cathode, or to etch a continuous coating.
The above features of the antimicrobial coatings of this invention have been found to ensure that the particulate size left behind by the antimicrobial coatings as the bioabsorbable material disappears, are less than about 2 xcexcm in size, and more preferably are less than 1 xcexcm in size.
The antimicrobial coating is formed in a crystalline form from antimicrobial metals with atomic disorder so as to produce an antimicrobial effect. The production of atomic disorder through physical vapour deposition techniques is described in the above mentioned PCT applications to Burrell et al. and as outlined below.
The antimicrobial metal is deposited as a thin metallic film on one or more surfaces of the bioabsorbable material by vapour deposition techniques. Physical vapour techniques, which are well known in the art, all deposit the metal from the vapour, generally atom by atom, onto a substrate surface. The techniques include vacuum or are evaporation, sputtering, magnetron sputtering and ion plying. The deposition is conducted in a manner to create atomic disorder in the coating as defined above. Various conditions responsible for producing atomic disorder are useful. These conditions are generally those which one has been taught to avoid in thin film deposition techniques, since the object of most thin film depositions is to create a defect free, smooth and dense film (see for example J. A. Thornton, J. Vac. Sci. Technol., Vol 11, (4); 666-670; and xe2x80x9cCoating Deposition by Sputteringxe2x80x9d in Deposition Technologies For Films and Coatings, Noyes Publications, N.J. 170-237, (1982)). The preferred conditions which are used to create atomic disorder during the deposition process include:
a low substrate temperature, that is maintaining the surface to be coated at a temperature such that the ratio of the substrate temperature to the melting point of the metal (in degrees Kelvin) is less than about 0.5, more preferably less than about 0.35 and most preferably less than about 0.3; and optionally one or both of:
a higher than normal working (or ambient) gas pressure, i.e. for vacuum evaporation: e-beam or are evaporation, greater than 0.01 mT, gas scattering evaporation (pressure plating) or reactive are evaporation, greater than 20 mT; for sputtering: greater than 75 mT; for magnetron sputtering: greater than about 10 mT; and for ion plating: greater than about 200 mT; and
maintaining the angle of incidence of the coating flux on the surface to be coated at less than about 75xc2x0, and preferably less than about 30xc2x0.
The metals used in the coating are those known to release ions etc. having an antimicrobial effect, as set out above. For bioabsorbable materials, the metal must also be biocompatible. Preferred metals include the noble metals Ag, Au, Pt, Pd, and Ir as well as Sn, Cu, Sb, Bi, and Zn or alloys or compounds of these metals or other metals. Most preferred is Ag or Au, or alloys or compounds of one or more of these metals. Particularly preferred is Ag.
For economic reasons, the thin metal film has a thickness no greater than that needed to provide release of metal ions on a sustainable basis over a suitable period of time. Within the preferred ranges of thicknesses set out above, the thickness will vary with the particular metal in the coating (which varies the solubility and abrasion resistance), and with the degree of atomic disorder in (and thus the solubility of) the coating. The thickness will be thin enough that the coating does not interfere with the dimensional tolerances or flexibility of the device for its intended utility.
The antimicrobial effect of the material so produced is achieved when the coating is brought into contact with an alcohol or a water-based electrolyte, thus releasing metal ions, atoms, molecules or clusters. The concentration of the metal species which is needed to produce an antimicrobial effect will vary from metal to metal. Generally, an antimicrobial effect is achieved with silver coatings in body fluids such as plasma, serum or urine at concentrations less than about 0.5-10 xcexcg/ml of silver species. Evidence of the antimicrobial effect of the material may be demonstrated by biological testing. Localized antimicrobial effect is demonstrated by zone of inhibition testing (see Example 1), whereas sustained release of the antimicrobial metal is illustrated by log reduction (see Examples 2 and 4).
The ability to achieve release of metal atoms, ions, molecules or clusters on a sustainable basis from a coating is dictated by a number of factors, including coating characteristics such as composition, structure, solubility and thickness, and the nature of the environment in which the device is used. As the level of atomic disorder is increased, the amount of metal species released per unit time increases. For instance, a silver metal film deposited by magnetron sputtering at T/Tm less than 0.5 and a working gas pressure of about 7 mTorr releases approximately ⅓ of the silver ions that a film deposited under similar conditions, but at 30 mTorr, will release over 10 days. Films that are created with an intermediate structure (ex. lower pressure, lower angle of incidence etc.) have Ag release values intermediate to these values as determined by bioassays. This then provides a method for producing controlled release metallic coatings. Slow release coatings are prepared such that the degree of disorder is low while fast release coatings are prepared such that the degree of disorder is high.
The time required for total dissolution will be a function of the film thickness, the composition of the film and the nature of the environment to which the film is exposed. The relationship in respect of thickness is approximately linear, i.e., a two-fold increase in film thickness will result in about a two-fold increase in longevity.
It is also possible to control the metal release from a coating by forming a thin film coating with a modulated structure. For instance, a coating deposited by magnetron sputtering such that the working gas pressure was low (ex. 15 mTorr) for 50% of the deposition time and high (ex. 30 mTorr) for the remaining time, has a rapid initial release of metal ions, followed by a longer period of slow release. This type of coating is extremely effective on devices such as urinary catheters for which an initial rapid release is required to achieve immediate antimicrobial concentrations followe by a lower release rate to sustain the concentration of metal ions over a period of weeks.
The substrate temperature used during vapour deposition should not be so low that annealing or recrystallization of the coating takes place as the coating warms to ambient temperatures or the temperatures at which it is to be used (ex. body temperature). This allowable xcex94T, that the temperature differential between the substrate temperature during deposition and the ultimate temperature of use, will vary from metal to metal. For the most preferred metals of Ag and Au, preferred substrate temperatures of xe2x88x9220xc2x0 C. to 200xc2x0 C., more preferably xe2x88x9210xc2x0 C. to 100xc2x0 C. are used.
Atomic disorder may also be achieved by preparing composite metal materials, that is materials which contain one or more antimicrobial metals in a metal matrix which includes atoms or molecules different from the antimicrobial metals, such that the inclusion of the different materials creates atomic disorder in the crystalline lattice.
The preferred technique for preparing a composite material is to co- or sequentially deposit the antimicrobial metal(s) with one or more other inert, biocompatible metals selected from Ta, Ti, Nb, Zn, V, Hf, Mo, Si, Al and alloys of these metals or other metal elements, typically other transition metals. Such inert metals have a different atomic radii from that of the antimicrobial metals, which results in atomic disorder during deposition. Alloys of this kind can also serve to reduce atomic diffusion and thus stabilize the disordered structure. Thin film deposition equipment with multiple targets for the placement of each of the antimicrobial and inert metals is preferably utilized. When layers are sequentially deposited the layer(s) of the inert metal(s) should be discontinuous, for example as islands within the antimicrobial metal matrix. The final ratio of the antimicrobial metal(s) to inert metal(s) should be greater than about 0.2. The most preferable inert metals are Ti, Ta, Zn and Nb. It is also possible to form the antimicrobial coating from oxides, carbides, nitrides, sulphides, borides, halides or hydrides of one or more of the antimicrobial metals and/or one or more of the inert metals to achieve the desired atomic disorder.
Another composite material may be formed by reactively co- or sequentially depositing, by physical vapour techniques, a reacted material into the thin film of the antimicrobial metal(s). The reacted material is an oxide, nitride, carbide, boride, sulphide, hydride or halide of the antimicrobial and/or inert metal, formed in situ by injecting the appropriate reactants, or gases containing same, (ex. air, oxygen, water, nitrogen, hydrogen, boron, sulphur, halogens) into the deposition chamber. Atoms or molecules of these gases may also become absorbed or trapped in the metal film to create atomic disorder. The reactant may be continuously supplied during deposition for codeposition or it may be pulsed to provide for sequential deposition. The final ratio of antimicrobial metal(s) to reaction product should be greater than about 0.2. Air, oxygen, nitrogen and hydrogen are particularly preferred reactants.
The above deposition techniques to prepare composite coatings may be used with or without the conditions of lower substrate temperatures, high working gas pressures and low angles of incidence set out above. One or more of these conditions are preferred to retain and enhance the amount of atomic disorder created in the coating.
C. Antimicrobial Powder for Bioabsorbable Materials
Antimicrobial powders for bioabsorbable materials are preferably nanocrystalline powders formed with atomic disorder. The powders either as pure metals, metal alloys or compounds such as metal oxides or metal salts, can be formed by vapour deposition, mechanical working, or compressing to impart atomic disorder, as set out below. Mechanically imparted disorder is conducted under conditions of low temperature (i.e. temperatures less than the temperature of recrystallization of the material) to ensure that annealing or recrystallization does not take place.
Nanocrystalline powders may comprise powders of the antimicrobial metal itself, or bioabsorbable powders which are coated with the antimicrobial metal, as demonstrated in Example 4 in which a chitosan powder is coated with silver.
Nanocrystalline powders of the antimicrobial metals may be prepared by several procedures as set out above, and as described in international Publication Nos. WO 93/23092 and WO 95/13704, both to Burrell et al.; or as otherwise known in the art. In general, nanocrystalline powders may be prepared as a nanocrystalline coating (formed with atomic disorder in accordance with procedures previously described) preferably of the above thickness, onto powdered biocompatible and bioabsorbable substrates such as chitin; or may be prepared as a nanocrystalline coating onto a substrate such as a cold finger or a silicon wafer, with the coating then scraped off to form a nanocrystalline powder.
Alternatively, fine grained or nanocrystalline powders of the anti-microbial metals may be cold worked to impart atomic disorder, whereby the material has been mechanically worked such as by milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material to ensure that atomic disorder is retained in the material (International Publication Nos. WO 93/23092 and WO 95/13704, both to Burrell et al.,). Nanocrystalline powders may be sterilized with gamma radiation as described below to maintain atomic disorder, hence the antimicrobial effect.
The prepared nanocrystalline powders may then be incorporated into or onto the bioabsorbable substrate by any methods known in the art. For example, the nanocrystalline powders may be layered onto the bioabsorbable substrate as a coating; mechanically mixed within the fibers of the bioabsorbable substrate; or impregnated into the bioabsorbable substrate by physical blowing. The quantity of nanocrytalline powder impregnating a bioabsorbable substrate could be adjusted accordingly to achieve a desired dose range. Alternatively, the nanocrystalline powder may be incorporated into a polymeric, ceramic, metallic matrix, or other matrices to be used as a material for the manufacture of bioabsorbable substrates, medical devices or parts of medical devices, or coatings therefor.
The antimicrobial effect of the nanocrystalline powders is achieved when the substrate, coated or impregnated with the nanocrystalline powder, is brought into contact with an alcohol or a water-based electrolyte, thus releasing the antimicrobial metal ions, atoms, molecules or clusters.
D. Sterilization
Bioabsorbable materials once coated with the antimicrobial coating or powder of an antimicrobial metal formed with atomic disorder are preferably sterilized without applying excessive thermal energy, which can anneal out the atomic disorder, thereby reducing or eliminating a useful antimicrobial effect. Gamma radiation is preferred for sterilizing such dressings, as discussed in International Publication No. WO 95/13704 to Burrell et al.
The sterilized materials should be sealed in packaging which excludes light penetration to avoid additional oxidation of the antimicrobial coating. Polyester peelable pouches are preferred. The shelf life of bioabsorbable, antimicrobial materials thus sealed should be over one year.
E. Use of Bioabsorbable Materials With Antimicrobial Coating or Powder
The antimicrobial coatings and powders of this invention are activated by contacting an alcohol or water-based electrolyte. If the bioabsorbable material is to be used in an application which does not provide exposure to an electrolyte, the material can be moistened with drops of sterile water or 70% ethanol, in order to activate the coating for release of antimicrobial metal species. In a dressing form, the bioabsorbable material can be secured in place with an occlusive or semi-occlusive layer, such as an adhesive film, which will keep the dressing in a moist environment.